We have profiled miRNA levels after acute and chronic cocaine administration in the mouse nucleus accumbens, one of cocaine's key target regions and identified a specific miRNA as a potential regulator of the mRNA for mouse brain derived neurotropic factor (BDNF). In particular, the miRNA recognizing element (MRE) for this miRNA was located in the long 3'untranslated region (UTR) of the mRNA for BDNF, which has been recently shown to be involved in neural plasticity, and that was selectively reduced by chronic cocaine administration in the mouse nucleus accumbens. BDNF has been previously implicated in the long-term effects of cocaine, including behavioral sensitization to the locomotor effects of cocaine, which is a classic paradigm of functional changes induced by repeated drug use. These findings suggest the overarching hypothesis of the present application that miRNAs play key regulatory roles in the neural plasticity induced by drugs of abuse and the specific hypothesis that the miRNA under study is a regulator of cocaine-induced behavioral plasticity. To test this hypothesis, in Specific Aim 1 we will investigate the role of this miRNA in cocaine-induced behavioral sensitization by use of chronic delivery by osmotic minipump of this miRNA or a specific antagonist or antimiR. We will also investigate whether cocaine-induced behavioral sensitization is impaired in mutant mice that lack the long BDNF 3'UTR. miRNA have the potential to regulate a large number of mRNAs and can therefore act as master regulator of specific genetic-modules. Therefore, Specific Aim 2 will address the sub-hypothesis that this specific miRNA is a master switch of a specific set of transcripts controlling aspects of cocaine-induced plasticity. To this aim, we will use a multidisciplinary strategy to investigate its regulation and targets in laser microdissected nucleus accumbens sub-regions. PUBLIC HEALTH RELEVANCE: The proposed studies will explore the role of microRNAs, a class of non-coding RNA, in the gene expression alterations in a model of cocaine-induced long-lasting functional changes. These studies will extend our understanding of the neurobiology of compulsive cocaine intake and may have implications for the identification of therapeutic targets for the treatment of cocaine addiction.